Methods and apparatus for determining formulation orientation of multi-layered pharmaceutical dosage forms

ABSTRACT

Rapid and accurate determination of the formulation orientation of multi-layer capsule-shaped tablets with respect to different internal formulation layers proximate to the opposite narrow and rounded ends of the tablets is required. By including an appropriate color scheme in multi-layer osmotic tablets, detection of the formulation orientation is achieved by detecting the color at a spot location on a side of the tablet corresponding to one or another formulation layer or to one or another interface of two formulation layers depending on the formulation orientation of the tablet.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 12/402,075 (nowallowed), which is a divisional of U.S. Ser. No. 09/324,343, filed Jun.2, 1999 (now U.S. Pat. No. 7,521,067, issued Apr. 21, 2009), whichclaims priority of Provisional application Ser. No. 60/087,787, filedJun. 3, 1998, the contents of each of which are herein incorporated byreference in their entirety.

BACKGROUND Field of the Invention

This invention pertains to pharmaceutical manufacturing and particularlyto determining the formulation orientation of multi-layer capsule shapedtablets with respect to different internal formulation layers proximateto the opposite narrow and rounded ends of the tablets. In particular,the present invention pertains to rapidly and accurately determining theformulation orientation of such tablets by including a specific colorscheme in the multi-layer design of the tablets that permits colordetection at a spot location on the side of the tablet to be used fordetermining the formulation orientation.

Description of the Related Art Including Information Disclosed Under 37CFR 1.97 and 1.98

Colorants may be used as an indicator of different formulation layers inmulti-layer dosage forms. Formulating different formulation layers withdifferent colorants is a useful quality control method that helps ensurethat the different formulation layers are distinguishable from eachother during the manufacturing process. Different colors included in thedifferent layers can be used to determine the formulation orientation ofthe dosage form with respect to the internal formulation layers whensuch a determination is required for a particular processing step. Anexample of such a processing step is drilling of a delivery port in amulti-layer osmotic dosage form. These dosage forms have an internalcompartment containing at least one drug containing layer, at least oneexpandable polymer-containing layer and, optionally, one or moredrug-free layers to produce a desired release pattern such as delayed orpulse release. The internal compartment is surrounded by a membrane thatis at least partially semipermeable and at least one delivery port isformed through the membrane at an appropriate location to permit releaseof drug-containing formulation from within the compartment. Theexpandable polymer-containing layer is known as a “push” layer 10because, following oral administration, fluid is imbibed through thesemipermeable membrane causing the drug-containing layer(s) and anyoptional drug-free layer(s) to form a dispensable formulation andcausing the polymer layer to expand and “push” the dispensableformulation through the delivery port.

Such osmotic dosage forms are typically manufactured by compressing thecomponent dispensable formulation-forming layer(s) and the push layer(s)together to form a multi-layer internal core, applying the semipermeablemembrane around the core and then drilling, typically with a laser, anappropriate delivery port. It will be appreciated that these dosageforms are internally non-symmetrical in that one or more portionscontain the dispensable formulation-forming layer(s) and one or moreportions contain the push layer(s). Generally, the push layer isadjacent to one end, the “push end,” of the tablet and the opposite endis the “dispensing end” that is proximal to the dispensableformulation-forming layer(s) within the dosage form. Proper operation ofthe dosage form requires that the delivery port be formed in thedispensing end of the dosage form and not in the push end of the dosageform. Thus, at some point prior to the laser drilling step, the internalformulation orientation of the dosage forms with respect to theseopposite ends must be determined to ensure that the delivery port isdrilled in the dispensing end, and not the push end, of each tablet.

Typically, multi-layer osmotic tablets have been produced inconventional tablet shapes such that a broad front surface encompassesthe dispensing end of the tablet and the opposite broad back surfaceencompasses the push end of the tablet. By including a colorant in atleast one formulation layer proximate to either the dispensing end orthe push end of the tablet, a contrast or color detector can be used todetermine the formulation orientation of the tablets with respect to thefront and back surfaces. Useful methods and apparatus for determiningthe formulation orientation of such tablets and for drilling thedelivery ports in the dispensing ends of the tablets are disclosed andclaimed in U.S. Pat. Nos. 5,294,770 and 5,399,828 owned by AlzaCorporation, each of which is incorporated in its entirety by referenceherein. In accord with these inventions, multi-layer osmotic tablets aresupplied in a manner that permits laser access to both the front and theback surface of the dosage form. A suitable color detector is used todetermine which surface encompasses the dispensing end of the tabletand, then, a laser controller directs the laser to drill at least onedelivery port in that end.

The above-described methods have been shown to be especiallysatisfactory for conventional tablet shapes where the dispensing end andthe push end of the tablet coincide with the front and back surfaces ofthe tablet. Because these surfaces are relatively broad and flat, acolor detector is able to accurately and rapidly determine the color andgenerate an appropriate signal to direct the laser. More recently, ithas been discovered that capsule shaped osmotic tablets having thedispensing end at one narrow and rounded end of the capsule-shapedtablet and the push end is at the opposite narrow and rounded end of thecapsule-shaped tablet are preferable to conventional tablet shapes forcertain applications. Unfortunately, because the narrow and rounded endsof the capsule-shaped tablets scatter a significant portion of lightdirected thereon, the above-described methods for determining theformulation orientation of the dosage forms by detecting the color atthe narrow and rounded ends corresponding to the dispensing end and pushend of the tablet are not satisfactory.

Pharmaceutical manufacturing in general requires high speed, efficiencyand accuracy and it is generally desirable to provide as many automatedsteps as possible. It would be an advance in the art to develop rapidand accurate automated color-detection methods and apparatus fordetermining the formulation orientation of multi-layer capsule-shapedosmotic dosage forms with respect to different internal formulationlayers proximate to the opposite narrow and rounded ends of the tablets.

SUMMARY

One aspect of the present invention pertains to providing methods andapparatus for determining the formulation orientation of multi-layercapsule shaped osmotic tablets. In a more particular aspect, the presentinvention pertains to rapidly and accurately determining the formulationorientation of such tablets by including a specific color scheme in thedesign of the tablets that permits color detection at a spot location onthe side of the tablet to be used for determining the formulationorientation.

In another aspect, the present invention pertains to methods of makingmulti-layer capsule-shaped osmotic tablets having an appropriate colorscheme to facilitate determination of the tablet formulation orientationby color detection at a spot location on the side of the tablet.

In accord with the above aspects, by including an appropriate colorscheme in multi-layer osmotic tablets, detection of the formulationorientation is achieved by detecting the color at a spot location on aside of the tablet corresponding to one or another formulation layerdepending on the formulation orientation of the tablet. An appropriatecolor scheme includes a first colorant in at least one of theformulation layers of the tablet. Preferably, a first colorant isincluded in at least one dispensable formulation-forming layer and asecond colorant, readily distinguishable from the first colorant, isincluded in at least one push layer of the tablet. To ensure significantcontrast between the dispensable formulation-forming layer(s) and thepush layer(s), it is preferred that the first colorant be “light,” asdefined elsewhere herein, so as to complement a non-colored dispensableformulation-forming layer, if present, and the second colorant be“dark,” as defined elsewhere herein, so as to be readily distinguishedfrom either the first colorant or no color. The first and secondcolorants may be the same colors provided that one is light and one isdark such that the colors are readily distinguishable, as definedelsewhere herein.

The above-described features and advantages, as well as others, willbecome more apparent from the following detailed disclosure of theinvention and the accompanying claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a cross-section view of a bi-layer osmotic dosage formrequiring determination of the formulation orientation in accord withthe present invention.

FIG. 2 is a cross-section view of a tri-layer osmotic dosage formrequiring determination of the formulation orientation in accord withthe present invention.

FIG. 3 is a schematic illustration of a method and apparatus in accordwith the present invention for determining the formulation orientationof a tri-layered osmotic capsule-shaped tablet.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

It has been discovered that capsule-shaped osmotic tablets wherein theformulation layers are oriented such that the dispensing end is at onenarrow and rounded end of the capsule-shaped tablet and the push end isat the opposite narrow and rounded end of the capsule-shaped tablet arepreferable for certain applications. For purposes of this disclosure,such multi-layer osmotic capsule-shaped tablets shall be referred to asCSTs (capsule-shaped tablets). The advent of CSTs has been found to posesome unique problems for determination of the formulation orientationwith a color detector. In the prior art, the differently-colored “ends”i.e., the dispensing end and the push end of the tablet, coincided withthe relatively broad and flat front and back surfaces of a conventionaltablet-shaped multi-layer osmotic tablet and color detection at one ofthese surfaces was satisfactory for determining the formulationorientation of the tablet. With CSTs, however, the dispensing end is atone narrow and rounded end of the capsule-shaped tablet and the push endis at the opposite narrow and rounded end. Although differently-colored,the ends are not as readily distinguishable because the ends are narrowand rounded resulting in significant scattering of impinging light fromthe color detector and reduced accuracy of the color determinations.

As described above, for some processing steps, such as laser drilling ofa drug delivery port into the dispensing end of an osmotic tablet, it isnecessary to identify the formulation orientation of the CST. Byincluding appropriate colorant(s) in the formulation layers, thedifferent ends are distinguishable by a color detector directed to aspot location on the side of the tablet rather than directed to an endof the tablet. It will be appreciated that a color contrast along theside of a CST can be achieved by adding a colorant to at least one ofthe formulation layers such that the colorant containing formulationlayer is readily distinguishable from the non-colored (ordifferently-colored) formulation layer(s).

Typically, a formulation layer that does not have colorant added will bewhite in color although, depending on the ingredients within theformulation layer, such a formulation layer may have a color other thanwhite. In any case, given the color of a formulation layer with nocolorant added, a distinguishable color can be added to the otherformulation layer. Alternatively, if desired, a first colorant can beincluded in one formulation layer and a readily distinguishable secondcolorant can be included in the other formulation layer.

“Color contrast,” as used herein, refers to a difference in colors thatis readily and rapidly distinguishable by a suitable color detector.“Readily distinguishable” colors, in general, include colors referred toherein as “light” colors, e.g., colors that complement a white color byhaving little contrast with a white color, and “dark” colors, e.g.,colors that contrast significantly with a white and/or light color, asdefined herein.

The phrase “differently-colored,” as used herein refers to the readilydistinguishable color contrast between either a dark color and no coloror a dark color and a light color. For purposes of this disclosure, aformulation layer having “no color” and a formulation layer having a“light color” are not considered to be “differently-colored” whereaseither of these layers are “differently-colored” from a dark coloredlayer.

A wide variety of coloring agents suitable for use in pharmaceuticaldosage forms are known and available. The concentration of a suitablecolorant that is added to a composition for forming a formulation layercan be widely varied to achieve many shades of color from very dark tovery light. Thus, a first and second colorant may be different colors ormay be the same color provided that one is used in a manner that effectsa light shade and the other a dark shade of the color so that thedifferent “colors” are readily distinguishable as defined herein.

As used herein, the term “colorant” or the phrase “coloring agent”refers to one or more substances, other than excipients, added to aformulation layer composition solely for the purpose of imparting colorto that formulation layer within the end product. The term “excipient”refers to pharmaceutically acceptable substances, other than colorantsor coloring agents, added to a pharmaceutical dosage form to givesuitable consistency or form to the dosage form including diluents,vehicles, carriers, disintegrants, binders, fillers, other processingaids and the like.

It has been discovered that determination of the formulation orientationof multi-layered osmotic capsule-shaped CSTs is accurately andefficiently accomplished by using color indicators for differentformulation layers and a color detector directed to a spot location on aside of the tablet rather than at an end of the tablet. By directing thecolor detector to a spot location on a side of the CST, more accuratecolor detection is possible because the side does not scatter theimpinging light as much as one of the rounded ends does. In addition,tablets of varying lengths and generally similar circumferences can beaccommodated with little or no adjustments to the apparatus when thedetection is performed at a spot location on the side of the tablet.

Suitable color detectors are known in the art and include various typesof incandescent and LED systems. Generally, such detectors includelighting means for generating and directing light to a circumscribedlocation on a surface and detecting means for recognizing color from thelightwaves that are reflected back to the detector from the spot.Display means for generating a signal, such as an electronic signal,that can be interpreted by a suitable processor are also included. Apreferred color detector for use in accord with the present invention isthe IDEC SAlJ Full Color Recognition Sensor, product of IDEC IZUMICorporation of Japan. This detector can be set to be responsive tobrightness as well as to color differentiation and, thus, can be used todiscriminate between many different colors and shades of colors. Bydirecting the sensor to a spot location on a side of the CST, in accordwith the present invention, the formulation orientation can beaccurately and rapidly determined from the color detected. Anappropriate signal is generated and interpreted by a suitable processorfor communication to a laser controller to thereby activate the laser asappropriate to drill a delivery port in the dispensing end of thetablet. Tablets that are properly oriented for drilling can betransported to a laser drilling station. Tablets that are improperlyoriented can either be removed from the transportation apparatus or canbe “passed over” at the laser drilling station and subsequentlyrecycled. Alternatively, as provided in a co-pending patent application,filed May 20, 1999, owned by Alza Corporation and entitled METHODS ANDAPPARATUS FOR UNIFORMLY ORIENTING PHARMACEUTICAL DOSAGE FORMS,improperly oriented tablets can have their orientation rectified andthen be transported to a laser drilling station in the properorientation.

An embodiment of a bi-layer oral osmotic dosage form 15 requiringdetermination of the formulation orientation in accord with the presentinvention is shown in cross-section in FIG. 1. The components are notdrawn to scale. The bi-layer CST core comprises a first component layer21, containing drug and selected excipients, and a second push layer 29,containing at least one fluid-expandable osmopolymer and optionallycontaining at least one osmagent along with selected excipients. Asindicated by the cross-hatching, the push layer 29 contains a darkcolorant such that this layer is readily distinguishable by colordetection on the side of the tablet from the drug-containing layer. Thedrug-containing layer may be non-colored or may contain a colorant thatprovides a light color to the layer. A semipermeable membrane 57surrounds the bi-layer tablet core to form a compartment and a suitablysized orifice 55 is formed through the semipermeable membrane and intothe first component layer 21 to permit drug formulation to be releasedfrom within the compartment. As described in more detail below, thesemipermeable membrane is sufficiently transparent or translucent topermit detection of the underlying differently-colored layers. Asillustrated, the orifice 55 is preferably formed in the narrow end ofthe dosage form comprising the first component layer. In operation, drugis released from the first drug-containing layer at a controlled releaserate for an extended time period. Although not shown in FIG. 1, animmediate-release dose of a drug may be provided by applying adrug-containing overcoat to a bi-layer dosage form, if desired, asdescribed elsewhere herein.

A preferred embodiment of a tri-layer oral osmotic dosage form 14requiring determination of the formulation orientation in accord withthe present invention is shown in cross-section in FIG. 2. The tri-layerCST core 30 comprises a first dispensable layer 20, containing aselected drug in a pharmaceutically acceptable form along with selectedexcipients but without any added colorant; a second dispensable layer18, containing a higher concentration of drug along with selectedexcipients and a light colorant; and a third push layer 28; containingat least one osmopolymer and optionally containing at least one osmagentalong with selected excipients and a colorant that imparts a dark colorthat is readily distinguishable from the color of the second layer. Asemipermeable membrane 56 surrounds the tri-layer tablet core to form acompartment and a suitably sized orifice 54 is formed through thesemipermeable membrane and into the first component layer to permit drugformulation to be released from within the compartment. As described inmore detail below, the semipermeable membrane is sufficientlytransparent or translucent to permit detection of the underlyingdifferently colored layers. As illustrated, the orifice 54 is preferablyformed in the narrow end of the dosage form comprising the firstcomponent layer. In operation, through cooperation of the tri-layerosmotic dosage form components, drug is successively released, in asustained and controlled manner, from the first drug-containing layerand then from the second drug-containing layer at a controlled and, inthis example, ascending release rate for an extended time period.

Following drilling of the orifice 54, the preferred embodiment furthercomprises an immediate-release dose of drug contained within an overcoat60 applied onto the surface of the tri-layer osmotic dosage form. Thedrug is mixed with suitable excipients such as, for example,hydroxypropylmethylcellulose, to prepare a solution for coating onto thesurface of the semipermeable membrane of the tri-layer osmotic dosageform that will rapidly dissolve and release drug followingadministration. Also, as shown in FIG. 2, it is also preferred toprovide an optional aesthetic overcoat 62 applied onto the surface ofthe drug-containing overcoat 60. As known in the art, such aestheticovercoats provide advantages including taste-masking, improvedappearance and “glidability” for facilitating swallowing and furtherprocessing steps such as printing, packaging, etc. An exemplaryembodiment of a tri-layer osmotic dosage form is detailed below inExample 1.

EXAMPLE 1

The first drug-containing layer contained the following (by weightpercent): 9.40% methylphenidate hydrochloride, 83.71% polyethylene oxide(Polyox N-80 brand product of Union Carbide, Danbury, Conn.), 5%polyvinylpyrrolidone (Kolidon 29-32 product of BASF Corp., Mt. Olive,N.J.); 1.34% succinic acid; 0.5% stearic acid; and 0.05% butylatedhydroxy toluene.

The second drug-containing layer contained the following (by weightpercent): 13.65% methylphenidate hydrochloride, 78.80% polyethyleneoxide (Polyox N-80 brand product of Union Carbide, Danbury, Conn.), 5%polyvinylpyrrolidone (Kolidon 29-32 product of BASF Corp., Mt. Olive,N.J.); 1.95% succinic acid; 0.5% stearic acid; 0.05% butylated hydroxytoluene; and 0.05% yellow ferric oxide, as coloring agent.

The third layer does not contain drug and is the push layer. The pushlayer contained the following (by weight percent): 73.7% high molecularweight polyethylene oxide (Polyox 303 brand product of Union Carbide,Danbury, Conn.), 20% sodium chloride; 5% polyvinylpyrrolidone (Kolidon29-32 brand product of BASF Corp., Mt. Olive, N.J.); 0.25% stearic acid;0.05% butylated hydroxy toluene; and 1% green ferric oxide, as coloringagent.

Each of the first component layer, second component layer and third pushlayer were separately prepared into granulated compositions in a fluidbed granulator. The granulated compositions were then compressed 2ssequentially on a rotary tablet press to produce the tri-layer CSTcores. For each dosage form, 40 mg of the first component layergranulation and 75 mg of the second component layer granulation werefirst sequentially filled and tamped at 100 newtons into the die. Then,90 mg of the third push layer granulation to the die was added to thedie and the final compression was performed at 1500 newtons.

The composition of the semipermeable membrane was 83% by weightcellulose acetate (CA 398-10, having an acetyl content of 39.8%, productof Eastman Chemical, Kingsport, Tenn.) and 17% by weight copolymer ofethylene and propylene oxide (Poloxamer 188 brand product of BASF Corp.,Mt. Olive, N.J., added as a flux-enhancer. The two ingredients weredissolved in a blend of 99.5% acetone and 0.5% water to form a 5% solidssolution. In a pan coater, the solution was then sprayed onto thetri-layer CST cores to a weight of 25.7 mg and a thickness of 4-5 mil.

As noted above, the semipermeable membrane is sufficiently translucentor transparent to permit determination of the formulation orientation byusing a color detector directed to a spot location on the side of theCST h accord with the present invention. Accordingly, followingdetermination of the formulation orientation, a 0.76 mm (40 mil) orificewas drilled through the semipermeable membrane at the narrow end of thecompartment proximate to the first component layer to thereby form thepreferred tri-layer osmotic dosage forms, each containing 14 mg ofmethylphenidate. Each dosage form was approximately 12 mm long with anapproximate diameter of 5.3 mm.

The drug overcoat for providing an immediate-release initial dose ofdrug contains approximately 30% by weight methylphenidate hydrochloride,approximately 70% by weight hydroxypropylmethylcellulose (Methocel E3brand name product of Dow Chemical Co., Midland, Mich.), and a traceamount of phosphoric acid (i.e., 20 ml of phosphoric acid added to 87 kgof drug in solution). An aqueous coating solution is prepared bydissolving and mixing the ingredients in water to form a solution with a10% solids composition. In a pan coater, the solution was then sprayedonto the semipermeable membranes of the tri-layer osmotic dosage formsto a weight of about 14.0 mg comprising an immediate-release dose ofmethylphenidate of about 4 mg.

The final aesthetic overcoat composition weighed 16.9 mg and containedan underlayer of Opadry II, yellow (brand name product of Colorcon, WestPoint, Pa. and an overlayer of Opadry, clear, with a trace amount ofcarnauba wax, a glidant, prepared and applied as follows: first, OpadryII (10%) is suspended in water (90%) and sprayed onto thedrug-overcoated dosage forms; next, clear Opadry (5%) is suspended inwater (95%) and sprayed onto the drug- and Opadry II-overcoated dosageforms; s finally, the dosage forms are tumbled in the coater with thecarnauba wax for ten minutes to allow about 100 ppm of wax to beuniformly distributed onto the clear Opadry overcoat.

Turning now to FIG. 3, a color detector 120 is shown in position todetect the color at a spot location on the side of a tri-layered osmoticCST 130 manufactured as described above in Example 1. The tri-layeredosmotic CST 130 has the push layer 140, containing 1% green ferric oxideas coloring agent, proximate to the push end 142. The firstdrug-containing layer 150, containing no colorant and appearing to bewhite, is proximate to the dispensing end 152. The seconddrug-containing layer 154, containing 0.05% yellow ferric oxide ascoloring agent, is positioned between the other two layers. The colorscheme has been adapted to provide a similar light-colored appearance tothe two drug-containing layers and a contrasting dark-colored appearanceto the push layer. This color scheme is preferred to provide a colorcontrast between the dispensable formulation-forming layers and the pushlayers and no color contrast between the dispensable formulation-forminglayers.

As shown in FIG. 3, the color detector is directed to a spot location ona side of the CST rather than to a location at either of the narrow androunded ends. In this manner, an accurate and efficient detection of thecolor of one or the other layer, or of the color interface between thetwo layers (depending on the spot location's relationship to theformulation layers), can be achieved. From the color detected, theformulation orientation of the CST can be determined.

It will be appreciated that the spot location can be selected, dependingon the size of the CST and the size of each formulation layer, such thatthe color is determined at a spot location on the tablet thatcorresponds to one or the other of the dispensable formulation-forminglayer(s) (or, possibly, to an interface of these two layers) or to thepush layer of the tablet depending on the formulation orientation.Accordingly, the color detector will detect either a light color(including a white color for a layer with no added colorant),corresponding to one or the other of the dispensable formulation-forminglayers or to an interface of these layers, or a dark color,corresponding to the push layer. Depending on the color detected, theformulation orientation of the CST can be determined.

It will be appreciated that the spot location is preferably selected,depending on the size of the CST and the size of each formulation layer,such that the color is determined at a location on the tablet that doesnot encompass an interface of differently-colored !_ayers, i.e., anon-colored or light colored layer with a dark colored layer. Forexample, if the push layer occupies substantially about half of theinternal compartment of the dosage form, a spot location near the centerof the tablet should be avoided. Rather, a spot location that isoff-center, toward one or the other end of the CST, is preferred suchthat the color detector sees either the color of the push layer or thereadily distinguishable color of one or another dispensable formulationforming layer, depending on the tablet orientation.

As shown in FIG. 3, a spot location is illustrated that is near thecenter of the CST but slightly toward the right end. In the exemplaryCST 130, the push layer occupies substantially half of the internalcompartment of the CST and the second drug-containing layer occupiesmost of the remaining half of the internal compartment. Accordingly,given the spot location illustrated, the color detector 120 will detecteither the dark-colored push layer or the light-colored second layer (asshown). If the spot location were moved to the center of the CST, thecolor detector would see a dark/light color interface and, the order ofthe colors would need to be analyzed to determine the formulationorientation of the CST. Since this analysis is more complicated than asimple dark/light color determination, it is preferred t select a spotlocation that will detect the color of one or another formulation layeras shown in FIG. 3.

While there has been described and pointed out features and advantagesof the invention, as applied to present embodiments, those skilled inthe art will appreciate that various modifications, changes, additions,and omissions in the descriptions within the specification can be madewithout departing from the spirit of the invention.

1. A method of preparing a multi-layer capsule-shaped tablet having apush end and a dispensing end for laser drilling of a delivery port insaid dispensing end, the method comprising the steps of: detecting theformulation orientation of the tablet by detecting the color at a spotlocation on a side of the tablet corresponding to one or anotherformulation layer depending on the formulation orientation of thetablet, wherein at least one layer contains a colorant; determining theformulation orientation of the tablet on the basis of the colordetected; passing the tablets through a tablet rectifier wherein theorientation of any improperly oriented tablets is rectified and theorientation of any properly oriented tablets is maintained; andcollecting the uniformly oriented tablets from said tablet rectifier fortransportation to a laser drilling station.
 2. The method of claim 1wherein the colorant is a dark colorant.
 3. The method of claim 2wherein the formulation layer containing the dark colorant does notcontain a drug ingredient and another formulation layer containing adrug ingredient also contains a light colorant.
 4. A method of making amulti-layer tablet comprising: adding a first colorant to oneformulation layer containing a drug ingredient proximately positioned ata dispensing end of the multi-layered tablet, the first colorant beingcomplementary to no color; adding a second colorant to at least oneformulation layer not containing any drug ingredient proximatelypositioned at a push end of the multi-layered tablet, the secondcolorant distinguishable from the first colorant or from no color;compressing the formulation layers into a capsule-shaped osmotic tabletsuch that the formulation orientation of the tablet can be determined bydetecting the color at a spot location on a side of the tabletcorresponding to one or another differently-colored formulation layerdepending on the formulation orientation of the tablet, and detectingthe formulation orientation of the tablet with a color detector directedat a spot location on a side of the tablet.